Oncostatin M (OM), a cytokine produced by macrophages and activated T
cells, has been shown to be a potent inducer of liver low density
lipoprotein receptor (LDLR) activity by increasing LDL uptake and cell
surface LDLR number in HepG2 cells. To investigate whether OM regulates the
transcription of the LDLR gene and if the effect is independent of the
sterol pathway, we examined the effects of OM on the promoter activity of
the LDLR gene and the expression of LDLR mRNA. HepG2 cells were transfected
with hybrid genes containing three different lengths of DNA fragments from
the 5' flanking region of the LDLR gene that were fused to the coding
region of the chloramphenicol acetyltransferase (CAT) gene. OM induced an
approximately 3-fold increase in CAT activities in pLDLR-CAT
vector-transfected cells that were incubated in lipoprotein-depleted medium
and a 6-fold increase in CAT activities when the transfected cells were
treated with sterols. OM stimulated similar increases in CAT activities in
HepG2 cells transfected with pLDLR-CAT 234, pLDLR-CAT 1563, and pLDLR-CAT
6500, suggesting that the essential cis-acting element that mediates the OM
effect is located within the 177 base pairs upstream of the transcription
start site of the LDLR gene. Examination of the regulation of the
endogenous LDLR mRNA expression by OM gave results similar to those in
transfected cells. OM increased the levels of mRNA of LDLR, regardless of
the presence or absence of lipoprotein and sterols. These data suggest that
the up-regulation of the LDLR by OM is at the transcriptional level through
a nonsterol mediated mechanism.